1. Field of the Invention
The present invention includes two processes which are useful in the production of midazolam.
2. Description of the Related Art
U.S. Pat. Nos. 4,280,957 and 4,377,523 disclose midazolam (VII) and processes for its production.
J. Heterocyclic Chem., 13, 433 (1976) discloses the conversion of the amino benzophenone starting material (I) to the corresponding nitro-nitrone (IV). The amino benzophenone (I) was transformed to the corresponding dihydroquinazoline which is then reacted with manganese dioxide to form the quinazoline (III). The quinazoline (III) is then transformed to the corresponding nitroolefin (IV) by reaction with lithium amide and nitromethane in dimethylsulfoxide.
J. Org. Chem., 43, 936 (1978) discloses the conversion of the nitroolefin (IV) to midazolam (VII). The nitroolefin (IV) is reduced to the amine (V) by catalytic hydrogenation. The amine (V) is transformed to the corresponding benzodiazepine (VI) by known methods. The benzodiazepine (VI) is then oxidized to midazolam (VII) in about 58% yield by use of manganese dioxide.
Aldrichimica Acta, 23(1), 13-19 (1990) discloses various reactions where "TPAP" is used as the catalyst for oxidation of alcohols. Example 41 discloses the oxidation of a 1-hydroxy-3-benzyloxycyclohexane derivative to the corresponding .alpha.,.beta.-unsaturated cyclohexanone. Tetrahedron Letters, 35(35), 6567-6570 (1994) discloses oxidation of indoline to produce indole by use of TPAP. The use of TPAP in the present invention is in a more complex ring system and it is advantageous to pretreat the TPAP with an alcohol before usage.
J. Org. Chem., 40(2), 153 (1975) discloses compound 10 which is similar to the midazolam-nitrone (IX) of the present invention but it does not have a fluorine atom required for pharmacological activity.